Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.
A genome-wide association study (GWAS) previously carried out in a cohort of 1,011 individuals with pediatric-onset inflammatory bowel disease (IBD) and 4,250 matched controls, identified and replicated a significantly associated, previously unreported locus on chromosome 20q13 carrying allelic variants. The locus is close to the TNFRSF6B gene, which encodes the Decoy Receptor 3 (DcR3) protein. Subsequently, sequencing of the TNFRSF6B gene in 528 pediatric IBD sufferers and 549 healthy control individuals uncovered several missense variants at the TNFRSF6B locus that are enriched in the IBD sufferers compared to controls, some of which may affect DcR3 secretion in cultured cells. (Cardinale et al., Genes and Immunity 14: 447-452 (2013).)
The present application further includes data showing that allelic variation in the TNFRSF6B locus is correlated with other autoimmune conditions including psoriasis and thyroiditis.
DcR3 binds to cytokines of the tumor necrosis factor (TNF) superfamily, namely TL1A (TNFSF15), LIGHT (TNFSF14) and Fas ligand (FASLG), and blocks their ability to stimulate their receptors. TL1A, for example, is also a ligand for the death-domain receptor 3 (DR3) protein. Binding of TL1A to DR3 may induce secretion of IFN-gamma by T cells and may activate the NF-κB pathway. DcR3 may compete with DR3 for TL1A binding, thus controlling its stimulatory effects on T cells. Genetic alterations in the DcR3 gene TNFRSF6B, for example those causing a reduction in DCR3 secretion or in ligand binding, as well as mutations affecting DcR3 expression levels, may cause unopposed inflammatory signals as DcR3 may be less effective in downregulating its ligands such as TL1A or LIGHT. Similarly, the inventors herein have recognized that genetic alterations in other genes in this pathway, such as the genes for DR3 (TNFRSF25), TL1A (TNFSF15), LIGHT (TNFSF14), FasL (FASLG), as well as Fas receptor (FASR; CD95), Herpes virus entry mediator A (HVEM or TNFRSF14), and lymphotoxins A and B (LTA and LTB) and their receptors, may similarly compromise the normal functioning of the DR3/DcR3 regulatory system.
Accordingly, the inventors have recognized that inhibitors of DcR3 ligands such as TL1A, LIGHT, and Fas ligand (FasL), for example anti-TL1A, anti-LIGHT, or anti-FasL antibodies or small molecule inhibitors, may be particularly useful in IBD subjects who have a DcR3 genetic alteration (i.e. that harbor a TNFRSF6B allelic variant) or who have a genetic alteration in another gene in this pathway. Data herein also show that DR3/DcR3 also may regulate the non-canonical NF-κB pathway. Thus, inhibitors of the non-canonical NF-κB pathway are further drug targets for autoimmune disease patients harboring genetic alterations in TNFRSF6B or in a TNFRSF6B/DcR3 pathway gene.